A variety of materials have been considered for non-viral gene delivery applications. These include a wide range of polyamines and lipids that can electrostatically bind and condense DNA or RNA for delivery to cells. Compared to viral gene delivery systems, these lipid and polyamine systems are generally safer because the genetic cargo is explicitly non-viral and is not integrated into the host genome, thereby avoiding the immunogenic and oncogenic tendencies of some viruses. Lipid and polyamine systems are also comparatively inexpensive and easy to prepare. A disadvantage of non-viral vectors, however, is poor gene delivery efficiency, which is typically orders of magnitude below the gene delivery efficiency of viruses. The inefficiency largely lies with extracelluar and intracellular barriers that exist between the site of administration and the nucleus of target cells. Cellular association, endocytosis, vector escape from the endosomal pathway, disassociation of the non-viral carrier and the plasmid DNA, migration of the plasmid DNA to the nucleus, and finally transcription all stand as obstacles to efficient gene delivery by lipid and polyamine systems.
Considerable effort has been devoted to the rational design of vectors that are able to contend with a small, well-defined subset of the identified extra- and intracellular barriers to gene delivery. For example, polyethyleneglycol (PEG) and other steric shielding materials have been attached to polymers to promote serum stability and sustained in vivo circulation Small molecules, proteins and antibodies have been incorporated into the design to permit receptor-mediated uptake by particular target cells. Polymers and lipids with various pH-sensitive and endosomolytic moieties have been produced to facilitate escape from the endosomal pathway. Nuclear localization signals have also been attached to DNA in attempt to aid nuclear delivery. While these strategies have been successful in tackling various individual barriers, the designs are, in general, too complicated or too molecule-specific to allow them to be used in conjunction with one another. Moreover, changing one aspect of a gene delivery vehicle can have significant implications on other areas of its performance. For these reasons, a single vector that can effectively incorporate several rational design elements into one package that addresses several of the critical barriers mentioned above has yet to be developed.
Self-assembly is a phenomenon in which a disordered system of components forms an organized structure as a consequence of specific, local interactions among the components. Self-assembly allows for the facile generation of a variety of unique molecular assemblies without laborious multistep conjugation chemistry. Instead, simple mixing of different components at different relative ratios is sufficient to produce a variety of structures. These assemblies can then be screened based on a range of parameters, including size, charge, function, and the like, to identify particular formulations that satisfy desired conditions or properties.
Self-assembly has been explored in the delivery of a variety of therapeutic agents, including genetic materials. For example, U.S. Pat. No. 7,018,609 (Hwang Pun et al.) describes the use of the host-guest interaction between cyclodextrin- and adamantane-modified materials to generate a targeted and stabilized polymer formulation for the delivery of therapeutic agents. However, there is a need in the art for a more effective non-viral delivery system exhibiting properties such as increased efficiency, stability and effective targeting abilities.